Amlodipine, Valsartan and Hydrochlorothiazide Tablets Type of Posting ...

Amlodipine, Valsartan and Hydrochlorothiazide Tablets

Type of Posting Posting Date Official Date Expert Committee Reason for Revision

Revision Bulletin 27?May?2016 01?Jun?2016 Chemical Medicines Monographs 2 Compliance

In accordance with the Rules and Procedures of the 2015-2020 Council of Experts, the Chemical Medicines Monographs 2 Expert Committee has revised the Amlodipine, Valsartan and Hydrochlorothiazide Tablets monograph. The purpose of this revision is to be consistent with the FDA-approved drug products and is described below.

? The acceptance criteria under Definition and Assay is widened from "NLT 95.0% and NMT 105.0%" to "NLT 92.5% and NMT 107.5%" for amlodipine, valsartan and hydrochlorothiazide.

? In the test for organic Impurities, the acceptance criteria for Benzothiadiazine related compound A is widened from NMT 0.4% to NMT 1.0%, Chlorothiazide and hydrochlorothiazide dimer from NMT 0.2% to NMT 0.50%, and the total degradation products is widened from NMT 1.5% to NMT 2.0%.

? A Dissolution Test 2 is added. The liquid chromatographic procedure is validated using an Inertsil ODS 3V brand of L1 column. The typical retention times for amlodipine, valsartan and hydrochlorothiazide are about 5.0 min and 7.5 min and 2.5 min respectively.

? A Dissolution Test 3 is added. The liquid chromatographic procedure is validated using an Oyster ODS 3 brand of L1 column. The typical retention times for hydrochlorothiazide and valsartan are about 2.3 min and 3.6 min respectively. The typical retention time for amlodipine is about 2.8 min.

Minor editorial changes have been made to update the monograph to the current USP style.

The Amlodipine, Valsartan and Hydrochlorothiazide Tablets Revision Bulletin supersede the currently official Amlodipine, Valsartan and Hydrochlorothiazide Tablets monograph. The Revision Bulletin will be incorporated in the USP 40?NF 35.

Should you have any questions, please contact Sujatha Ramakrishna, Ph.D., MBA. Senior Scientific Liaison (301?816?8349 or sxr@).

C163375_150708, C163875_150721-M4852-CHM22015, Rev. 0 20160527

Revision Bulletin Official June 1, 2016

Amlodipine 1

.

Amlodipine, Valsartan, and Hydrochlorothiazide Tablets

DEFINITION

Change to read:

Amcolondtiapinine?,.NVLaTlsa9r2t.a5n%, aannddHNyMdrToc1h0lo7r.o5t%hi?az(iRdB e1-JuTna-2b01le6)tseach

of the labeled amounts of amlodipine (C20H25ClN2O5), valsartan (C24H29N5O3), and hydrochlorothiazide (C7H8ClN3O4S2).

IDENTIFICATION ? A. The UV absorption spectra of the amlodipine, val-

sartan, and hydrochlorothiazide peaks of Sample solution A, Sample solution B, and Sample solution C and those of the Standard solution exhibit maxima and minima at the same wavelengths, as obtained in the Assay. ? B. The retention times of the amlodipine, valsartan, and hydrochlorothiazide peaks of Sample solution A, Sample solution B, and Sample solution C correspond to those of the Standard solution, as obtained in the Assay.

ASSAY

Change to read:

? PROCEDURE Use amber glassware for all solutions containing drug substances. Solution A: Acetonitrile, water, and phosphoric acid (50:950:1) Solution B: Acetonitrile, water, and phosphoric acid (950:50:1) Mobile phase: See Table 1.

Time (min)

0 3 6 10 10.1 15

Table 1

Solution A (%) 95 50 40 5 95 95

Solution B (%) 5 50 60 95 5 5

Diluent: Acetonitrile and water (500:500) 0.1% Phosphoric acid: Water and phosphoric acid (1000:1) Standard solution: 0.14 mg/mL of USP Amlodipine Besylate RS, 0.064 mg/mL of USP Valsartan RS, and 0.025 mg/mL of USP Hydrochlorothiazide RS in Diluent Sample stock solution: Transfer NLT 10 Tablets into a suitable volumetric flask. Add 0.1% Phosphoric acid to 4% of the total volume to disperse the Tablets. Sonicate for 10 min. Add 4% of the total volume of acetonitrile, swirl to mix, and add 60% of the total volume

of Diluent. Sonicate for 20 min. Dilute with Diluent to volume to obtain solutions of nominal concentrations stated in Table 2. Centrifuge, and use the clear supernatant.

Tablet Strength Amlodipine/ Valsartan/ Hydrochlorothiazide (mg/mg/

mg)

5/160/12.5

10/160/12.5

5/160/25

10/160/25

10/320/25

Table 2

Nominal Concentra-

tion of

Amlodipine (mg/mL)

0.1

0.2

0.1

0.2

0.1

Nominal Concentra-

tion of Valsartan

(mg/mL) 3.2 3.2 3.2 3.2 3.2

Nominal Concentra-

tion of Hydrochlorothia-

zide (mg/mL)

0.25

0.25

0.5

0.5

0.25

Sample solution A: Nominally equivalent to 0.1 mg/

mL of amlodipine in Diluent from Sample stock solution

Sample solution B: Nominally equivalent to 0.064 mg/

mL of valsartan in Diluent from Sample stock solution

Sample solution C: Nominally equivalent to

0.025 mg/mL of hydrochlorothiazide in Diluent from

Sample stock solution

Chromatographic system

(See Chromatography 621, System Suitability.)

Mode: LC

Detector

Assay: 225 nm Identification test A:

Diode array, ?UV 200?400

.

? nm (RB 1-Jun-2016)

Column: 4.6-mm ? 15-cm; 3-?m packing L1

Column temperature: 40?

Flow rate: 1.5 mL/min

Injection volume: 10 ?L

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0 for amlodipine, valsartan,

and hydrochlorothiazide

Relative standard deviation: NMT 2.0% for

amlodipine, valsartan, and hydrochlorothiazide

Analysis

Samples: Standard solution, Sample solution A, Sample

solution B, and Sample solution C

Calculate the percentage of the labeled amount of

amlodipine (C20H25ClN2O5) in the portion of Tablets

taken:

Result = (rU/rS) ? (CS/CU) ? (Mr1/Mr2) ? 100

rU = peak response of amlodipine from Sample solution A

rS = peak response of amlodipine from the Standard solution

CS = concentration of USP Amlodipine Besylate RS in the Standard solution (mg/mL)

CU = nominal concentration of amlodipine in Sample solution A (mg/mL)

Mr1 = molecular weight of amlodipine, 408.88 Mr2 = molecular weight of amlodipine besylate,

567.05 Calculate the percentage of the labeled amount of valsartan (C24H29N5O3) in the portion of Tablets taken:

Result = (rU/rS) ? (CS/CU) ? 100

rU = peak response of valsartan from Sample solution B

rS = peak response of valsartan from the Standard solution

CS = concentration of USP Valsartan RS in the Standard solution (mg/mL)

?2016 The United States Pharmacopeial Convention All Rights Reserved. C163375_150708, C163875_150721-M4852-CHM22015, Rev. 0 20160527

2 Amlodipine

Revision Bulletin Official June 1, 2016

CU = nominal concentration of valsartan in Sample solution B (mg/mL)

Calculate the percentage of the labeled amount of hydrochlorothiazide (C7H8ClN3O4S2) in the portion of Tablets taken:

Result = (rU/rS) ? (CS/CU) ? 100

rU = peak response of hydrochlorothiazide from

Sample solution C

rS = peak response of hydrochlorothiazide from the

Standard solution

CS = concentration of USP Hydrochlorothiazide RS

in the Standard solution (mg/mL)

CU = nominal concentration of hydrochlorothiazide

in Acceptance

Sample criteria:

so?lu.9t2io.n5%C ?(1m0g7/.m5%L)?

(RB

1-Jun-2016)

PERFORMANCE TESTS

Change to read:

? ? ? DISSOLUTION 711

Test 1

.

(RB 1-Jun-2016)

Buffer: Dissolve 6.805 g of monobasic potassium

phosphate and 0.896 g of sodium hydroxide in

1000 mL of water. Adjust with 0.2 N sodium hydrox-

ide or 1 M phosphoric acid to a pH of 6.8.

Medium: Buffer; 900 mL

Apparatus 2: 50 rpm for 5/160/12.5, 10/160/12.5,

5/160/25, and 10/160/25 (mg/mg/mg) of Tablet

strengths (amlodipine/valsartan/hydrochlorothiazide);

55 rpm for 10/320/25 (mg/mg/mg) of Tablet

strengths (amlodipine/valsartan/hydrochlorothiazide)

Time: 30 min

Solution A: Acetonitrile, water, and phosphoric acid

(50:950:1)

Solution B: Acetonitrile, water, and phosphoric acid

(950:50:1)

Mobile phase: See Table 3.

Time (min) 0.00 2.50 2.51 4.00

Table 3

Solution A (%) 67 23 67 67

Solution B (%) 33 77 33 33

Diluent: 1 mg/mL of polysorbate 80 in Buffer Standard stock solution A: 0.07 mg/mL of USP

Amlodipine Besylate and 0.124 mg/mL of USP Hydrochlorothiazide RS. Initially dissolve with 4% of the total volume of methanol, and dilute with Diluent to volume. Standard stock solution B: 3.2 mg/mL of USP Valsartan RS in methanol Standard solution: 0.014 mg/mL of USP Amlodipine Besylate RS, 0.16 mg/mL of USP Valsartan RS, and 0.0248 mg/mL of USP Hydrochlorothiazide RS in Diluent from Standard stock solution A and Standard stock solution B, respectively Sample solution: Pass a portion of the solution under test through a suitable filter of 0.45-?m pore size. Discard at least the first 10 mL of the filtrate. Chromatographic system (See Chromatography 621, System Suitability.)

Mode: LC Detector: UV 250 nm Column: 4.6-mm ? 5-cm; 3-?m packing L1 Column temperature: 30? Flow rate: 1.5 mL/min Injection volume: 5 ?L for 10/320/25 (mg/mg/mg) of Tablet strengths (amlodipine/valsartan/hydrochlorothiazide); 10 ?L for 5/160/12.5, 10/160/12.5, 5/

160/25, and 10/160/25 (mg/mg/mg) of Tablet strengths (amlodipine/valsartan/hydrochlorothiazide) System suitability Sample: Standard solution Suitability requirements Resolution: NLT 3.0 between amlodipine and

valsartan Tailing factor: NMT 2.0 for amlodipine, valsartan,

and hydrochlorothiazide Relative standard deviation: NMT 2.0% for amlodipine, valsartan, and hydrochlorothiazide Analysis Samples: Standard solution and Sample solution Calculate the percentage of the labeled amount of amlodipine (C20H25ClN2O5) dissolved:

Result = (rU/rS) ? CS ? V ? (Mr1/Mr2) ? (1/L1) ? 100

rU = peak response of amlodipine from the Sample solution

rS = peak response of amlodipine from the Standard solution

CS = concentration of USP Amlodipine Besylate RS in the Standard solution (mg/mL)

V = volume of Medium, 900 mL Mr1 = molecular weight of amlodipine, 408.88 Mr2 = molecular weight of amlodipine besylate,

567.05 L1 = label claim for amlodipine (mg/Tablet) Calculate the percentage of the labeled amount of valsartan (C24H29N5O3) dissolved:

Result = (rU/rS) ? CS ? V ? (1/L2) ? 100

rU = peak response of valsartan from the Sample solution

rS = peak response of valsartan from the Standard solution

CS = concentration of USP Valsartan RS in the Standard solution (mg/mL)

V = volume of Medium, 900 mL L2 = label claim for valsartan (mg/Tablet) Calculate the percentage of the labeled amount of hydrochlorothiazide (C7H8ClN3O4S2) dissolved:

Result = (rU/rS) ? CS ? V ? (1/L3) ? 100

rU = peak response of hydrochlorothiazide from the Sample solution

rS = peak response of hydrochlorothiazide from the Standard solution

CS = concentration of USP Hydrochlorothiazide RS in the Standard solution (mg/mL)

V = volume of Medium, 900 mL L3 = label claim for hydrochlorothiazide (mg/

Tablet) Tolerances: NLT 75% (Q) of the labeled amount of amlodipine (C20H25ClN2O5) is dissolved, NLT 80% (Q)

of the labeled amount of valsartan (C24H29N5O3) is dissolved, and NLT 80% (Q) of hydrochlorothiazide

?T(eCs7tH28:ClNIf3tOh4eS2p)riosdduicsstoclvoemdp. lies with this test, the .

labeling indicates that the product meets USP Dissolution Test 2.

?2016 The United States Pharmacopeial Convention All Rights Reserved. C163375_150708, C163875_150721-M4852-CHM22015, Rev. 0 20160527

Revision Bulletin Official June 1, 2016

Amlodipine 3

Medium: Proceed as directed under Dissolution Test 1, 900 mL. Apparatus 2 For Tablets labeled to contain amlodipine/valsartan/hydrochlorothiazide, 5/160/12.5, 10/160/ 12.5, 5/160/25, 10/160/25, and 5/80/12.5 (mg/ mg/mg): 50 rpm For Tablets labeled to contain amlodipine/valsartan/hydrochlorothiazide, 10/320/25 (mg/mg/ mg): 55 rpm Time: 30 min for valsartan and hydrochlorothiazide, 45 min for amlodipine Buffer: Mix 7.0 mL of triethylamine with 1000 mL of water. Adjust with phosphoric acid to a pH of 3.0. Solution A: Acetonitrile and Buffer (10:90). Solution B: Acetonitrile and Buffer (90:10). Mobile phase: See Table 4.

Time (min)

0 7 8 15

Table 4

Solution A (%) 90 30 90 90

Solution B (%) 10 70 10 10

Standard stock solution A: 0.35 mg/mL of USP Amlodipine Besylate RS prepared as follows. Initially dissolve in 10% of the final volume of methanol and dilute with Medium to volume. Standard stock solution B: 1.6 mg/mL of USP Valsartan RS in methanol Standard stock solution C: 0.7 mg/mL of USP Hydrochlorothiazide RS prepared as follows. Initially dissolve in 25% of the final volume of methanol and dilute with Medium to volume. Standard solution: (L1/1000) mg/mL of amlodipine, L2/1000) mg/mL of valsartan, and (L3/1000) mg/mL of hydrochlorothiazide in Diluent from Standard stock solution A, Standard stock solution B, and Standard stock solution C, where L1 is the label claim of amlodipine in mg/Tablet, L2 is the label claim of valsartan in mg/Tablet, and L3 is the label claim of hydrochlorothiazide in mg/Tablet Sample solution: Pass a portion of the solution under test through a suitable filter of 1-?m pore size. Chromatographic system (See Chromatography 621, System Suitability.) Mode: LC Detector: UV 237 nm Column: 4.6-mm ? 15-cm; 5-?m packing L1 Temperatures Autosampler: 10? Column: 50? Flow rate: 1.5 mL/min Injection volume: 20 ?L System suitability Sample: Standard solution Suitability requirements Tailing factor: NMT 2.0 for each peak Relative standard deviation: NMT 2.0% for each

peak Analysis Samples: Standard solution and Sample solution Calculate the percentage of the labeled amount of

amlodipine (C20H25ClN2O5) dissolved:

Result = (rU/rS) ? CS ? V ? (Mr1/Mr2) ? (1/L1) ? 100

rU = peak response of amlodipine from the Sample solution

rS = peak response of amlodipine from the Standard solution

CS = concentration of USP Amlodipine Besylate RS in the Standard solution (mg/mL)

V = volume of Medium, 900 mL Mr1 = molecular weight of amlodipine, 408.88 Mr2 = molecular weight of amlodipine besylate,

567.05 L1 = label claim for amlodipine (mg/Tablet) Calculate the percentage of the labeled amount of valsartan (C24H29N5O3) dissolved:

Result = (rU/rS) ? CS ? V ? (1/L2) ? 100

rU = peak response of valsartan from the Sample solution

rS = peak response of valsartan from the Standard solution

CS = concentration of USP Valsartan RS in the Standard solution (mg/mL)

V = volume of Medium, 900 mL L2 = label claim for valsartan (mg/Tablet) Calculate the percentage of the labeled amount of hydrochlorothiazide (C7H8ClN3O4S2) dissolved:

Result = (rU/rS) ? CS ? V ? (1/L3) ? 100

rU = peak response of hydrochlorothiazide from the Sample solution

rS = peak response of hydrochlorothiazide from the Standard solution

CS = concentration of USP Hydrochlorothiazide RS in the Standard solution (mg/mL)

V = volume of Medium, 900 mL L3 = label claim for hydrochlorothiazide (mg/

Tablet) Tolerances: NLT 75% (Q) of the labeled amount of amlodipine (C20H25ClN2O5) is dissolved, NLT 80% (Q) of the labeled amount of valsartan (C24H29N5O3) is dissolved, and NLT 80% (Q) of the labeled amount of hydrochlorothiazide (C7H8ClN3O4S2) is dissolved. Test 3: If the product complies with this test, the labeling indicates that the product meets USP Dissolution Test 3. Medium: Dissolve 6.80 g of monobasic potassium phosphate in 1000 mL of water. Adjust with 10% sodium hydroxide solution to a pH of 6.8.; 1000 mL for valsartan and hydrochlorothiazide; 900 mL for amlodipine Apparatus 2: 50 rpm for valsartan and hydrochlorothiazide; 55 rpm for amlodipine in Tablets labeled to contain amlodipine/valsartan/hydrochlorothiazide, 10/ 320/25 (mg/mg/mg); and 50 rpm for amlodipine in Tablets labeled to contain amlodipine/valsartan/hydrochlorothiazide, 5/160/12.5, 10/160/12.5, 5/160/25, 10/160/25, and 5/80/12.5 (mg/mg/mg) Times: 30 min for valsartan and hydrochlorothiazide, 45 min for amlodipine Solution A: Acetonitrile, trifluoroacetic acid and water (10:0.1:90) Solution B: Acetonitrile, trifluoroacetic acid and water (90:0.1:10) Mobile phase: See Table 5.

Time (min) 0.01

2.5

Table 5

Solution A (%) 90 10

Solution B (%) 10 90

?2016 The United States Pharmacopeial Convention All Rights Reserved. C163375_150708, C163875_150721-M4852-CHM22015, Rev. 0 20160527

4 Amlodipine

Revision Bulletin Official June 1, 2016

Time (min)

3.0 5.0

Table 5 (Continued)

Solution A (%) 90 90

Solution B (%) 10 10

Diluent: Acetonitrile and water (50:50) Standard stock solution A: 0.15 mg/mL of USP Amlodipine Besylate RS in Medium prepared as follows. Initially dissolve and sonicate in 5% of the final volume of Diluent and dilute with Medium to volume. Standard stock solution B: 1.6 mg/mL of USP Valsartan RS in Medium prepared as follows. Initially dissolve and sonicate in 20% of the final volume of Diluent and dilute with Medium to volume. Standard stock solution C: 0.25 mg/mL of USP Hydrochlorothiazide RS in Medium prepared as follows. Initially dissolve and sonicate in 10% of the final volume of Diluent and dilute with Medium to volume. Standard solution: (L1/1000) mg/mL of amlodipine, (L2/1000) mg/mL of valsartan, and (L3/1000) mg/mL of hydrochlorothiazide in Diluent from Standard stock solution A, Standard stock solution B, and Standard stock solution C, where L1 is the label claim of amlodipine in mg/Tablet, L2 is the label claim of Valsartan in mg/Tablet, and L3 is the label claim of hydrochlorothiazide in mg/Tablet. Sample solution: Pass a portion of the solution under test through a suitable filter of 0.45-?m pore size. Discard at least the first few mL of the filtrate. Chromatographic system (See Chromatography 621, System Suitability.) Mode: LC Detector: UV 237 for amlodipine and UV 270 nm

for valsartan and hydrochlorothiazide Column: 4.6-mm ? 10-cm; 5-?m packing L1 Flow rate: 1.5 mL/min Injection volume: 10 ?L System suitability Sample: Standard solution Suitability requirements

Tailing factor: NMT 2.0 for each peak Relative standard deviation: NMT 2.0% for each peak Analysis Samples: Standard solution and Sample solution Calculate the percentage of the labeled amount of amlodipine (C20H25ClN2O5) dissolved:

Result = (rU/rS) ? CS ? V ? (Mr1/Mr2) ? (1/L1) ? 100

rU = peak response of amlodipine from the Sample solution

rS = peak response of amlodipine from the Standard solution

CS = concentration of USP Amlodipine Besylate RS in the Standard solution (mg/mL)

V = volume of Medium, 900 mL Mr1 = molecular weight of amlodipine, 408.88 Mr2 = molecular weight of amlodipine besylate,

567.05 L1 = label claim for amlodipine (mg/Tablet) Calculate the percentage of the labeled amount of valsartan (C24H29N5O3) dissolved:

Result = (rU/rS) ? CS ? V ? (1/L2) ? 100

rU = peak response of valsartan from the Sample solution

rS = peak response of valsartan from the Standard solution

CS = concentration of USP Valsartan RS in the Standard solution (mg/mL)

V = volume of Medium, 1000 mL L2 = label claim for valsartan (mg/Tablet) Calculate the percentage of the labeled amount of hydrochlorothiazide (C7H8ClN3O4S2) dissolved:

Result = (rU/rS) ? CS ? V ? (1/L3) ? 100

rU = peak response of hydrochlorothiazide from the

Sample solution

rS = peak response of hydrochlorothiazide from the

Standard solution

CS = concentration of USP Hydrochlorothiazide RS

in the Standard solution (mg/mL)

V = volume of Medium, 1000 mL

L3 = label claim for hydrochlorothiazide (mg/

Tablet)

Tolerances

For Tablets labeled to contain amlodipine/

valsartan/hydrochlorothiazide, 5/160/12.5, 10/

160/12.5, 5/160/25, and 10/160/25 (mg/mg/

mg): NLT 75% (Q) of the labeled amount of

amlodipine (C20H25ClN2O5) is dissolved, NLT 80% (Q)

of the labeled amount of valsartan (C24H29N5O3) is

dissolved, and NLT 80% (Q) of the labeled amount

of hydrochlorothiazide (C7H8ClN3O4S2) is dissolved.

For Tablets labeled to contain amlodipine/val-

sartan/hydrochlorothiazide, 5/160/25, and 10/

320/25 (mg/mg/mg): NLT 70% (Q) of the labeled

amount of amlodipine (C20H25ClN2O5) is dissolved,

NLT 80% (Q) of the labeled amount of valsartan

(C24H29N5O3) is dissolved, and NLT 80% (Q) of the

labeled amount of hydrochlorothiazide

?

(C7H8ClN3O4S2) is UNIFORMITY OF DOSAGE

dUisNsIoTlSve9d0.?5(R:B

1-Jun-2016)

Meet the

requirements

IMPURITIES

Change to read:

? ORGANIC IMPURITIES Use amber glassware for all solutions containing drug substances. Mobile phase, Diluent, Sample solution A, Sample solution B, Sample solution C, and Chromatographic system: Proceed as directed in the Assay. System suitability solution: 0.02 mg/mL each of USP Benzothiadiazine Related Compound A RS and USP Valsartan Related Compound B RS, 0.005 mg/mL of USP Amlodipine Related Compound A RS, 0.14 mg/mL of USP Amlodipine Besylate RS, 0.064 mg/mL of USP Valsartan RS, and 0.025 mg/mL of USP Hydrochlorothiazide RS in Diluent Sensitivity solution: 0.14 ?g/mL of USP Amlodipine Besylate RS, 0.064 ?g/mL of USP Valsartan RS, and 0.025 ?g/mL of USP Hydrochlorothiazide RS in Diluent Standard solution: 0.0005 mg/mL of USP Amlodipine Related Compound A RS, 0.0001 mg/mL of USP Benzothiadiazine Related Compound A RS, 0.0003 mg/ mL of USP Amlodipine Besylate RS, 0.00015 mg/mL of USP Valsartan RS, and 0.00005 mg/mL of USP Hydrochlorothiazide RS in Diluent System suitability Samples: System suitability solution, Sensitivity solution, and Standard solution Suitability requirements Signal-to-noise ratio: NLT 10 for amlodipine, valsartan, and hydrochlorothiazide, Sensitivity solution

?2016 The United States Pharmacopeial Convention All Rights Reserved. C163375_150708, C163875_150721-M4852-CHM22015, Rev. 0 20160527

Revision Bulletin Official June 1, 2016

Amlodipine 5

Resolution: NLT 2.0 between any adjacent peaks of benzothiadiazine related compound A, hydrochlorothiazide, amlodipine related compound A, amlodipine, valsartan related compound B, and valsartan, System suitability solution Relative standard deviation: NMT 5.0% for amlodipine related compound A, benzothiadiazine related compound A, amlodipine, valsartan, and hydrochlorothiazide, Standard solution Analysis Samples: Sample solution A, Sample solution B, Sample solution C, and Standard solution Calculate the percentage of amlodipine related compound A in the portion of Tablets taken:

Result = (rU/rS) ? (CS/CU) ? (Mr1/Mr2) ? 100

rU = peak response of amlodipine related compound A from Sample solution A

rS = peak response of amlodipine related compound A from the Standard solution

CS = concentration of USP Amlodipine Related Compound A RS in the Standard solution (mg/mL)

CU = nominal concentration of amlodipine in Sample solution A (mg/mL)

Mr1 = molecular weight of amlodipine related compound A free base, 406.86

Mr2 = molecular weight of amlodipine related compound A fumarate, 522.93

Calculate the percentage of any valsartan related degradation product in the portion of Tablets taken:

Result = (rU/rS) ? (CS/CU) ? 100

rU = peak response of any valsartan related degradation product from Sample solution B

rS = peak response of valsartan from the Standard solution

CS = concentration of USP Valsartan RS in the Standard solution (mg/mL)

CU = nominal concentration of valsartan in Sample solution B (mg/mL)

Calculate the percentage of benzothiadiazine related compound A in the portion of Tablets taken:

Result = (rU/rS) ? (CS/CU) ? 100

rU = peak response of benzothiadiazine related compound A from Sample solution C

rS = peak response of benzothiadiazine related compound A from the Standard solution

CS = concentration of USP Benzothiadiazine Related Compound A RS in the Standard solution

(mg/mL)

CU = nominal concentration of hydrochlorothiazide

Calculate

in Sample solution the percentage of

C?c(mhlogr/omthL)iazide

and

.

hydrochlorothiazide dimer? (RB 1-Jun-2016) in the portion

of Tablets taken:

Result = (rU/rS) ? (CS/CU) ? 100

rU

= peak response of ?chlorothiazide or .

hydrochlorothiazide dimer? (RB 1-Jun-2016) from

Sample solution C

rS = peak response of hydrochlorothiazide from the

Standard solution

CS = concentration of USP Hydrochlorothiazide RS

in the Standard solution (mg/mL)

CU = nominal concentration of hydrochlorothiazide

in Sample solution C (mg/mL)

Calculate the percentage of each unspecified degradation product in the portion of Tablets taken:

Result = (rU/rS) ? (CS/CU) ? (Mr1/Mr2) ? 100

rU = peak response of each unspecified degradation

product from Sample solution A

rS = peak response of amlodipine from the

Standard solution

CS = concentration of USP Amlodipine Besylate RS

in the Standard solution (mg/mL)

CU = nominal concentration of amlodipine in

Sample solution A (mg/mL)

Mr1 = molecular weight of amlodipine, 408.88

Mr2 = molecular weight of amlodipine besylate,

567.05 Acceptance criteria:

? ? See

Table 6.

.

(RB 1-Jun-2016) Disre-

gard amlodipine ethyl analog peak, valsartan related

compound B peak, and any peaks below 0.1%.

? ? Table 6 .

(RB 1-Jun-2016)

Name

Relative Retention

Time

Acceptance Criteria, NMT (%)

Benzothiadiazine related

compound Aa

.

? ? Chlorothiazide .

(RB 1-Jun-

2016)b.

Hydrochlorothiazide

0.60

0.62 0.64

? ? 1.0 .

(RB 1-Jun-2016)

? ? 0.50 .

(RB 1-Jun-2016)

--

Devaleryl valsartanc .

?Hydrochlorothiazide . ? dimer (RB 1-Jun-2016)d.

Amlodipine related compound Ae

.

Amlodipine

0.71 0.89

0.96 1.00

0.2

? ? 0.50 .

(RB 1-Jun-2016)

0.5 --

Valsartan related

degradation

product 1f .

1.04

0.2

Amlodipine ethyl analogg

1.08

--

.

Valsartan related compound Bh

1.22

--

.

Valsartan related

degradation

product 2f .

1.27

0.2

Valsartan

1.36

--

Valsartan related degradation product 3f

.

1.51

0.2

a 4-Amino-6-chloro-1,3-benzenedisulfonamide.

? ? .

b 6-Chloro-2 H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide.

.

.

(RB 1-

Jun-2016)

c N-{[2'-(1H-Tetrazole-5-yl)biphenyl-4-yl]methyl}-L-valine.

?. d 6-Chloro-N-[(6-chloro-7-sulfamoyl-2,3-dihydro-4H-1,2,4-

.

.

benzothiadiazine-4-yl 1,1-dioxide)methyl]3,4-dihydro-2H-1,2,4-

? benzothiadiazine-7-sulfonamide 1,1-dioxide. (RB 1-Jun-2016)

e 3-Ethyl, 5-methyl [2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-6-meth.

yl-3,5-pyridinedicarboxylate].

f These are specified unidentified degradation products. No information is .

available about chemical structures or chemical names for these impurities.

? g Diethyl 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-1,4.

dihydropyridine-3,5-dicarboxylate. Process related impurity given for in-

.

formation only. (RB 1-Jun-2016)

? ? h (S)-N-Butyryl-N-{[2'-(1-H-tetrazole-5-yl)-biphenyl-4-yl]-methyl}-valine.

.

.

? Process related impurity given for information only. (RB 1-Jun-2016)

i Benzenesulfonic acid is the counter ion to the amlodipine, and peaks at .

RRT of 0.33 and 0.42 are not considered as degradation products.

?2016 The United States Pharmacopeial Convention All Rights Reserved. C163375_150708, C163875_150721-M4852-CHM22015, Rev. 0 20160527

6 Amlodipine

Revision Bulletin Official June 1, 2016

? ? Table 6 .

(RB 1-Jun-2016) (Continued)

Name

Relative Retention

Time

Acceptance Criteria, NMT (%)

Valsartan related degradation product 4f

.

1.62

0.2

Any other unspecified degradation producti

--

0.2

.

Total degradation products

--

? ? 2.0 .

(RB 1-Jun-2016)

a 4-Amino-6-chloro-1,3-benzenedisulfonamide.

? ? .

b 6-Chloro-2 H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide.

.

.

(RB 1-

Jun-2016)

c N-{[2'-(1H-Tetrazole-5-yl)biphenyl-4-yl]methyl}-L-valine.

?. d 6-Chloro-N-[(6-chloro-7-sulfamoyl-2,3-dihydro-4H-1,2,4-

.

.

benzothiadiazine-4-yl 1,1-dioxide)methyl]3,4-dihydro-2H-1,2,4-

? benzothiadiazine-7-sulfonamide 1,1-dioxide. (RB 1-Jun-2016)

e 3-Ethyl, 5-methyl [2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-6-meth.

yl-3,5-pyridinedicarboxylate].

f These are specified unidentified degradation products. No information is .

available about chemical structures or chemical names for these impurities.

? g Diethyl 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-1,4.

dihydropyridine-3,5-dicarboxylate. Process related impurity given for in-

.

formation only. (RB 1-Jun-2016)

? ? h (S)-N-Butyryl-N-{[2'-(1-H-tetrazole-5-yl)-biphenyl-4-yl]-methyl}-valine.

.

.

? Process related impurity given for information only. (RB 1-Jun-2016)

i Benzenesulfonic acid is the counter ion to the amlodipine, and peaks at .

RRT of 0.33 and 0.42 are not considered as degradation products.

ADDITIONAL REQUIREMENTS ? PACKAGING AND STORAGE: Store at controlled room tem-

perature in tight containers in a dry place.

Add the following:

?? LABELING: When more than one Dissolution test is .

given, the labeling states the Dissolution test used only if

Test 1 is not used.? (RB 1-Jun-2016)

? USP REFERENCE STANDARDS 11 USP Amlodipine Besylate RS USP Amlodipine Related Compound A RS 3-Ethyl, 5-methyl [2-(2-aminoethoxymethyl)4-(2-chlorophenyl)-6-methyl-3,5-pyridinedicarboxylate] fumarate. C20H23ClN2O5 ? C4H4O4 522.93 USP Benzothiadiazine Related Compound A RS 4-Amino-6-chloro-1,3-benzenedisulfonamide. C6H8ClN3O4S2 285.73 USP Hydrochlorothiazide RS USP Valsartan RS

?2016 The United States Pharmacopeial Convention All Rights Reserved. C163375_150708, C163875_150721-M4852-CHM22015, Rev. 0 20160527

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